The present invention relates to a method for the preparation of N-Formyl-L-Aspartic anhydride (F-Asp=O) which is used to prepare peptide sweeteners which contain a terminal aspartic acid moiety such as .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM).
The aspartyl containing dipeptides are produced through a coupling reaction in which aspartic acid is joined with a second amino acid or derivatives thereof such as L-phenylalanine or its methyl ester. These coupling reactions require an amino protecting group attached to the aspartic acid moiety such as formyl, acetyl, acetoacetyl, benzyl, substituted and unsubstituted carbobenzoxy, t-butoxy carbonyl and the hydrohalide salt. The amino protecting group, often referred to in the art as the N-protecting group, for purposes of this disclosure shall be referred to as N-formyl since the formyl moiety functions as the blocking agent. Formylated aspartic anhydride is a widely used starting material and its process has been described extensively. See U.S. Pat. Nos. 4,173,562, 3,933,781 and 3,962,207 all of which are incorporated herein by reference.
Coupling reactions are carried out in a solvent and are common in several patented processes for the production of .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM); see U.S. Pat. No. 3,962,207 to Uchiyama, U.S. Pat. No. 4,173,562 to Bachman and EPO Patent No. 127,411 to Yaichi et al., all of which are incorporated herein by reference.
N-Formyl-L-aspartic anhydride is usually produced from a reaction mixture of aspartic acid, a large excess of formic acid and acetic anhydride. The excess amount of formic acid must at some point be removed by distillation and separated from acetic acid which adds to the cost of the final product. The present invention avoids these extra distillation and separation procedures.